JPWO2018155051A1 - リピドa - Google Patents
リピドa Download PDFInfo
- Publication number
- JPWO2018155051A1 JPWO2018155051A1 JP2019501132A JP2019501132A JPWO2018155051A1 JP WO2018155051 A1 JPWO2018155051 A1 JP WO2018155051A1 JP 2019501132 A JP2019501132 A JP 2019501132A JP 2019501132 A JP2019501132 A JP 2019501132A JP WO2018155051 A1 JPWO2018155051 A1 JP WO2018155051A1
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- Prior art keywords
- lipid
- fatty acid
- chain
- lps
- acid chain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 title claims abstract description 160
- 239000002671 adjuvant Substances 0.000 claims abstract description 59
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229960002442 glucosamine Drugs 0.000 claims abstract description 43
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- 125000005313 fatty acid group Chemical group 0.000 claims abstract 14
- 239000002158 endotoxin Substances 0.000 claims description 128
- 229920006008 lipopolysaccharide Polymers 0.000 claims description 126
- 241000588986 Alcaligenes Species 0.000 claims description 46
- ATRNZOYKSNPPBF-UHFFFAOYSA-N 3-hydroxytetradecanoic acid Chemical group CCCCCCCCCCCC(O)CC(O)=O ATRNZOYKSNPPBF-UHFFFAOYSA-N 0.000 claims description 24
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 20
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical group CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 19
- ATRNZOYKSNPPBF-CYBMUJFWSA-N (R)-3-hydroxytetradecanoic acid Chemical compound CCCCCCCCCCC[C@@H](O)CC(O)=O ATRNZOYKSNPPBF-CYBMUJFWSA-N 0.000 claims description 13
- MUCMKTPAZLSKTL-LLVKDONJSA-N (R)-3-hydroxylauric acid Chemical group CCCCCCCCC[C@@H](O)CC(O)=O MUCMKTPAZLSKTL-LLVKDONJSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
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- MUCMKTPAZLSKTL-UHFFFAOYSA-N 3-hydroxylauric acid Chemical group CCCCCCCCCC(O)CC(O)=O MUCMKTPAZLSKTL-UHFFFAOYSA-N 0.000 claims description 2
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 11
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- A—HUMAN NECESSITIES
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- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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Abstract
Description
1.グルコサミン二糖鎖と脂肪酸鎖の複合体からなるリピドAであって、グルコサミン二糖鎖の2位及び2'位に3-ヒドロキシ脂肪酸鎖が結合しており、当該3-ヒドロキシ脂肪酸鎖の少なくとも一方に、3-ヒドロキシ脂肪酸鎖からなる二次脂肪酸鎖がさらに結合していることを特徴とするリピドA。
2.さらに、グルコサミン二糖鎖の3位及び3'位の少なくとも1つに3-ヒドロキシ脂肪酸鎖が結合していることを特徴とする、前項1に記載のリピドA。
3.脂肪酸鎖が、3-ヒドロキシミリスチン酸鎖、3-ヒドロキシラウリン酸鎖及びカプリン酸鎖から選択されるいずれかである、前項1又は2に記載のリピドA。
4.グルコサミン二糖鎖の2位及び2'位と、3位及び3'位の少なくとも1つに結合する脂肪酸鎖が3-ヒドロキシミリスチン酸である、前項1〜3のいずれかに記載のリピドA。
5.グルコサミン二糖鎖の2位及び2'位に結合する少なくとも一方の二次脂肪酸鎖が3-ヒドロキシラウリン酸鎖である、前項1〜4のいずれかに記載のリピドA。
6.グルコサミン二糖鎖と脂肪酸鎖の複合体からなるリピドAであって、グルコサミン二糖鎖の2位、2'位、3位及び3'位に3-ヒドロキシミリスチン酸鎖が結合しており、当該グルコサミン二糖鎖の2位に結合する3-ヒドロキシミリスチン酸鎖にカプリン酸鎖からなる二次脂肪酸鎖が結合しており、当該グルコサミン二糖鎖の2'位に結合する3-ヒドロキシミリスチン酸鎖に3-ヒドロキシラウリン酸鎖からなる二次脂肪酸鎖が結合していることを特徴とするリピドA。
7.グルコサミン二糖鎖の4'位にリン酸基が結合してなる前項1〜6のいずれかに記載のリピドA。
8.リピドAが、以下の化11に示す化合物11である、前項1〜7のいずれかに記載のリピドA。
10.アルカリゲネス属由来のリポ多糖に含まれるリピドAであって、グルコサミン二糖鎖の2位及び2'位に結合する2種の脂肪酸鎖が、二次脂肪酸鎖を含む脂肪酸鎖であることを特徴とするリピドA。
11.リピドAが、化学合成方法により作製されたリピドAである前項1〜8のいずれかに記載のリピドA。
12.前項1〜11のいずれかに記載のリピドAを含むリポ多糖。
13.前項1〜11のいずれかに記載のリピドAを含むアジュバント組成物及び/又は免疫賦活化剤。
14.前項13に記載のアジュバント組成物及び/又は免疫賦活化剤を含むワクチン組成物。
15.前項1〜11のいずれかに記載のリピドAの作製方法。
1)市販のLPS抽出キット(iNtRON Biotechnology Inc.)をアルカリゲネスの乾燥菌体に対して使用する。
2)アルカリゲネスの乾燥菌体を石油エーテルとクロロホルムとフェノールの混合溶媒や加熱されたフェノールと水の混合溶媒を用いてLPSを抽出した後、デオキシリボヌクレアーゼ、リボヌクレアーゼ、プロテイナーゼによって処理し、透析及び体積排除カラム(General Electric Company: Sephacryl S-400 HR)によって精製する。
抽出したアルカリゲネス由来LPSを、例えば酢酸水溶液で処理し、生じた沈殿物を水で洗浄することでアルカリゲネスのリピドAを得ることが可能である。
化合物1の3位にミリスチン酸誘導体2を2-メチル-6-ニトロ安息香酸無水物(MNBA)とN,N-ジメチル-4-アミノピリジン(DMAP)、N,N-ジイソプロピルエチルアミン(DIPEA)を用いて導入し、化合物3を得る。化合物3の2'位のトリクロロエトキシカルボニル(Troc)基を亜鉛-銅合金を用いて切断した後、遊離となったアミノ基に、二次脂肪酸鎖としてラウリン酸を有するミリスチン酸誘導体4を、1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム 3-オキシドヘキサフルオロホスフェート(HATU)とDMAPを用いることで導入し、化合物5を得る。化合物5の2位のアリルオキシカルボニル基(Alloc)をテトラキス(トリフェニルホスフィン)パラジウム(0)とN-(トリメチルシリル)ジメチルアミン(TMSDMA)を用いて切断する。続いて、遊離となったアミノ基に、二次脂肪酸鎖としてカプリン酸を有するミリスチン酸誘導体である化合物6を、HATUとDMAPを用いて導入し、化合物7を得る。化合物7の3'位のパラメトキシベンジル基(MPM)を、2,3-ジクロロ-5,6-ジシアノ-p-ベンゾキノン(DDQ)と2,6-ジ-tert-ブチルピリジンによって切断し、遊離となった水酸基にミリスチン酸誘導体2をMNBAとDMAP及びDIPEAを用いて導入し、化合物8を得る。化合物8の4'位及び6'位のベンジリデン基にトリフルオロ酢酸(TFA)を作用させて切断し、トリチルクロライドとピリジンを用いて6'位にトリチル基を導入し、化合物9を得る。化合物9の1位のアリル基を、(1,5)-(シクロオクタジエン)-ビス(メチルジフェニルホスフィン)イリジウム(1)ヘキサフルオロホスフェートを用いて異性化させた後、ヨウ素と水を作用させることで切断し、化合物10を得る。化合物10に対し、ジベンジル-N,N-ジイソプロピルホスホロアミダイト、テトラゾール、続いて、ジメチルジオキシラン(DMDO)を作用させることで1位と4'位にリン酸基を導入した。最終脱保護として、水酸化パラジウムを用いた接触水素化を行うことで、全てのベンジル基及びトリチル基を切断し、アルカリゲネス由来リピドAと同じ構造からなる化合物11を得ることができる。
本実施例では、アルカリゲネス属フェカーリス(Alcaligenes faecalis)のLPSを構成するリピドAの構造解析を行った。前記アルカリゲネスの乾燥菌体を石油エーテル、クロロホルム及びフェノールの混合溶媒や加熱されたフェノールと水の混合溶媒を用いて抽出し、デオキシリボヌクレアーゼ、リボヌクレアーゼ、プロテイナーゼによって処理し、透析及び体積排除カラム(General Electric Company: Sephacryl S-400 HR)によってLPSを分離精製した。分離したLPSを、酢酸水溶液にて処理し、生じた沈殿物を水で洗浄することでリピドAを得た。
本実施例では、アルカリゲネス属フェカーリス(Alcaligenes faecalis)からLPSを抽出し、各種作用を確認した。本実施例では、市販のLPS抽出キット(iNtRON Biotechnology Inc.)を用いてLPSを抽出し、LPS試料とした。比較例として使用する大腸菌由来のLPSは大腸菌O111由来LPSを用いた。
アルカリゲネス由来LPSのTLR4アゴニスト活性を、TLR4ノックアウト(KO)マウスの骨髄由来樹状細胞を用いて確認した。また、TLR2 KOマウスについても確認した。
野生型マウスとして、10週齢の雌のBalb/c(ニホンクレア)を用いた。TLR2 KOマウス又はTLR4 KOマウスとして、10週齢の雌のC57/BL6(オリエンタルバイオ)を用いた。
大腸菌由来LPSによる樹状細胞でのIL-6の産生に対して、アルカリゲネス由来LPSが及ぼす影響を確認した。上記1の野生型マウスの樹状細胞に各濃度のアルカリゲネス由来LPSを加え、さらに100pg/mLの大腸菌由来LPSを加えて37℃で48時間培養し、IL-6の産生を上記1と同手法により測定した。その結果、アルカリゲネス由来LPSは大腸菌由来LPSによるIL-6の産生を阻害せず、大腸菌由来LPSに対するアンタゴニスト作用がないことが確認された(図14)。
1μgの卵白アルブミン(Ovalbumin:Sigma, A5503、以下単に「OVA」ともいう)を抗原とし、アジュバントとしてアルカリゲネス又は大腸菌由来のLPS(100μg)、あるいは200μLのアラムアジュバント(Imject Alum Adjuvant:Thermo Fisher Scientific Inc, 77161、以下単に「Alum」ともいう)を8週齢(雌)のBalb/cマウス(ニホンクレア)に各々投与したときのOVA特異抗体産生能を調べた。回収した血清中のOVA特異的抗体を、ELISA法にて測定した。
10μgのOVAと、100μgのアルカリゲネス若しくは大腸菌由来のLPS、又は200μLのAlum(Thermo Fisher Scientific Inc)を8週齢(雌)のBalb/cマウス(ニホンクレア)の背部皮下に投与し、各マウスの体重の変化及びIgE産生量を確認した。体重は経時的に測定し、7日後に血清を回収し、ELISA法にてOVA特異的IgE抗体を、DSマウスIgE ELISA(OVA)キット(DSファーマメディカル株式会社)を用いて測定した。
10週齢(雌)のBalb/cマウス(ニホンクレア)に、1.5 mgの大腸菌由来又はアルカリゲネス由来のLPSを腹腔内投与したときの直腸体温を直腸温度計で毎時間測定した。さらに、各LPS投与した7時間後に肺組織を摘出し、HE染色にて肺組織に及ぼす影響を確認した。PBSで処理したものをMockとした。
本実施例では、本発明のリピドAの合成方法について説明する。グルコサミン塩酸塩を出発原料として化合物1を経ることで本発明のリピドAを合成した(図19参照)。
1H NMRスペクトル測定はJEOL ECA 500 MHz NMR spectrometerを用いて、指定した溶媒中、30℃で行った。化学シフトはテトラメチルシラン(0 ppm)を基準物質としてδ値で表した。質量分析はmicrOTOF-QIII/compact(BRUKER)又はOrbitrap XL(登録商標)(Thermo Fisher Scientific)をそれぞれ用いて測定した。薄層クロマトフラフィーはKieselgel 60F254 Plates(Merck, 0.25 mm thickness)を用いた。中圧シリカゲルカラムクロマトグラフィーは、指定した溶媒系でKieselgel 60(Merck, 0.040-0.063 mm)を用い、0.1-0.3 MPaにて行った。ゲル浸透クロマトグラフィーは指定した溶媒系でSephadex LH-20 を用い、大気圧下にて行った。特に言及しない限り、非水中の反応はアルゴン雰囲気下で行った。
MS (ESI-LIT-orbitrap MS, positive) Calcd. for C65H83Cl3N2O16 [M+Na]+ : 1275.4700, Found 1275.4723
MS (ESI-LIT-orbitrap MS, positive) Calcd. for C95H136N2O18 [M+Na]+ : 1615.9680, Found 1615.9742
MS (ESI-LIT-orbitrap MS, positive) Calcd. for C115H176N2O19 [M+Na]+ : 1912.2760, Found 1912.2801
MS (ESI-LIT-orbitrap MS, positive) Calcd. for C128H200N2O20 [M+Na]+ : 2108.4587, Found 2108.4644
本実施例では、実施例2に記載の方法と同手法により抽出したアルカリゲネス属フェカーリス由来LPSについて、マウスでのOVA特異的免疫応答の増強を確認した。比較例として使用する大腸菌由来LPSは大腸菌O111由来LPSを用いた。
本実施例では、リピドAについてマウスでのOVA特異的抗体産生能の増強を確認した。本実施例のリピドAとして実施例3で合成されたリピドA(化合物11)を用いた。なお、リピドA(化合物11)はアルカリゲネス属フェカーリス由来リピドAと同等の構造を有する。
本実施例では実施例5に示したリピドA(化合物11)について、マウス樹状細胞の活性化を確認した。活性化はサイトカイン(IL-6)の産生能により確認した。
本実施例では実施例5に示したリピドA(化合物11)について、ヒトの末梢血単核細胞の活性化を確認した。末梢血単核細胞の活性化はサイトカイン(IL-6、IL-1β)の産生能により確認した。
Claims (15)
- グルコサミン二糖鎖と脂肪酸鎖の複合体からなるリピドAであって、グルコサミン二糖鎖の2位及び2'位に3-ヒドロキシ脂肪酸鎖が結合しており、当該3-ヒドロキシ脂肪酸鎖の少なくとも一方に、3-ヒドロキシ脂肪酸鎖からなる二次脂肪酸鎖がさらに結合していることを特徴とするリピドA。
- さらに、グルコサミン二糖鎖の3位及び3'位の少なくとも1つに3-ヒドロキシ脂肪酸鎖が結合していることを特徴とする、請求項1に記載のリピドA。
- 脂肪酸鎖が、3-ヒドロキシミリスチン酸鎖、3-ヒドロキシラウリン酸鎖及びカプリン酸鎖から選択されるいずれかである、請求項1又は2に記載のリピドA。
- グルコサミン二糖鎖の2位及び2'位と、3位及び3'位の少なくとも1つに結合する脂肪酸鎖が3-ヒドロキシミリスチン酸である、請求項1〜3のいずれかに記載のリピドA。
- グルコサミン二糖鎖の2位及び2'位に結合する少なくとも一方の二次脂肪酸鎖が3-ヒドロキシラウリン酸鎖である、請求項1〜4のいずれかに記載のリピドA。
- グルコサミン二糖鎖と脂肪酸鎖の複合体からなるリピドAであって、グルコサミン二糖鎖の2位、2'位、3位及び3'位に3-ヒドロキシミリスチン酸鎖が結合しており、当該グルコサミン二糖鎖の2位に結合する3-ヒドロキシミリスチン酸鎖にカプリン酸鎖からなる二次脂肪酸鎖が結合しており、当該グルコサミン二糖鎖の2'位に結合する3-ヒドロキシミリスチン酸鎖に3-ヒドロキシラウリン酸鎖からなる二次脂肪酸鎖が結合していることを特徴とするリピドA。
- グルコサミン二糖鎖の4'位にリン酸基が結合してなる請求項1〜6のいずれかに記載のリピドA。
- リピドAが、以下の化11に示す化合物11である、請求項1〜7のいずれかに記載のリピドA。
- リピドAが、アルカリゲネス属由来のリポ多糖に含まれるリピドAである請求項1〜8のいずれかに記載のリピドA。
- アルカリゲネス属由来のリポ多糖に含まれるリピドAであって、グルコサミン二糖鎖の2位及び2'位に結合する2種の脂肪酸鎖が、二次脂肪酸鎖を含む脂肪酸鎖であることを特徴とするリピドA。
- リピドAが、化学合成方法により作製されたリピドAである請求項1〜8のいずれかに記載のリピドA。
- 請求項1〜11のいずれかに記載のリピドAを含むリポ多糖。
- 請求項1〜11のいずれかに記載のリピドAを含むアジュバント組成物及び/又は免疫賦活化剤。
- 請求項13に記載のアジュバント組成物及び/又は免疫賦活化剤を含むワクチン組成物。
- 請求項1〜11のいずれかに記載のリピドAの作製方法。
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BIOCHEMISTRY(MOSCOW), 2006, VOL.71, NO.7, PP.759-766, JPN6021043398, ISSN: 0004628632 * |
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